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Different Disclosed Probabilities to Receive an Antiemetic Equally Decrease Subjective Symptoms in an Experimental Placebo Study: To Be or Not to Be Sure

      Abstract

      Purpose

      The purpose of this study was to examine whether the disclosed probability of receiving an antiemetic affects nausea.

      Methods

      Forty-eight healthy participants (mean [SD] age, 26.8 [5.4] years; 50% female) were exposed to 5 × 2 minutes of nauseogenic body rotations on 2 days. On day 2, participants were randomized to 3 experimental groups that were given different instructions concerning the probability of receiving an antiemetic remedy (100%, 50%, or 0% probability), whereas all received an inert substance. Subjective symptoms, behavioral (rotation tolerance) measures, and physiologic (electrogastrogram) measures of nausea were assessed and mediator and moderator analyses performed for effects of expectations and psychological characteristics on outcomes.

      Findings

      Disclosed probabilities of both 100% and 50% significantly reduced subjective symptoms of nausea in an equal manner compared with the 0% probability group from day 1 to day 2. This effect was found for neither rotation tolerance nor myoelectric gastric activity. Expectations and psychological characteristics did not affect the results found. Post hoc analyses revealed that women only seem to be susceptible to this placebo effect.

      Implications

      Nausea is susceptible to placebo effects independent of the disclosed probability of receiving a drug and of explicit expectations. In line with placebo research, this effect is probably attributable to central mechanisms, and it is speculated that it could be related to the reward circuitry and social interactions.

      Key words

      Introduction

      Research about placebo effects aims to further our understanding of the underlying mechanisms, to minimize their influences in clinical trials, but to harness and maximize them in clinical practice.
      • Enck P.
      • Bingel U.
      • Schedlowski M.
      • Rief W.
      The placebo response in medicine: minimize, maximize or personalize?.
      In general, placebo effects arise from expectations and learning through conditioning and social observation, but it is still difficult to explain the large interindividual variance of placebo responses between persons
      • Horing B.
      • Weimer K.
      • Muth E.R.
      • Enck P.
      Prediction of placebo responses: a systematic review of the literature.
      and conditions.
      • Weimer K.
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      Age and sex as moderators of the placebo response - An evaluation of systematic reviews and meta-analyses across medicine.
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      Placebo effects in psychiatry: mediators and moderators.
      Furthermore, one of the important questions is whether and how results from experimental placebo research can be transferred to clinical trials and practice.
      • Schedlowski M.
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      Neuro-bio-behavioral mechanisms of placebo and nocebo responses: implications for clinical trials and clinical practice.
      This question is linked to effects of the perceived probability of receiving a potent drug or a placebo in clinical trials.
      • Enck P.
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      • Weimer K.
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      The placebo response in clinical trials: more questions than answers.
      Two fundamental differences have been pointed out between double-blind randomized clinical trials (RCTs) with patients and experimental studies with healthy volunteers that bear difficulties for this translation. First, in classic RCTs, participants are randomized with a 50% probability to a drug or a placebo group not knowing in which group they are, whereas in most placebo mechanism studies participants are told convincingly (or conditioned) that they receive “a potent drug” with a 100% probability of inducing a placebo effect. This conceptual difference may have led to a significant difference in effect sizes for placebo analgesia among 23 RCTs (mean effect size = 0.15) and 14 experimental studies (mean effect size = 0.95) in a meta-analysis.
      • Vase L.
      • Riley 3rd, J.L.
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      A comparison of placebo effects in clinical analgesic trials versus studies of placebo analgesia.
      Second, the desire and motivation for symptom relief could be different between patients with a disease or disorder, maybe even a chronic condition, and healthy volunteers who take part in an experimental study in which a symptom is induced for some minutes or hours only and who are paid for their participation or receive credit points.
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      • Robinson M.E.
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      The contributions of suggestion, desire, and expectation to placebo effects in irritable bowel syndrome patients.
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      Motivation and placebos: do different mechanisms occur in different contexts?.
      Reviews and meta-analyses of RCTs and experimental studies have repeatedly found that placebo effects vary based on the probability of being randomized to an active drug or a placebo group. As far as we know, Diener et al
      • Diener H.C.
      • Dowson A.J.
      • Ferrari M.
      • et al.
      Unbalanced randomization influences placebo response: scientific versus ethical issues around the use of placebo in migraine trials.
      were the first who pointed to the problem that an unbalanced randomization of more patients to drug groups than to the placebo group may inflate placebo effects in migraine RCTs. They compared a study with a randomization of 16:1 for drug to placebo with other RCTs with ratios of 1:1 to 8:1, which also tested the same drugs for migraine treatment. They found that the drug responses were nearly the same but placebo responses increased up to fourfold, probably because of higher expectations of patients to receive a drug. This association between the disclosed probability of receiving a drug or placebo has also been found for other conditions, such as RCTs for depression,
      • Papakostas G.I.
      • Fava M.
      Does the probability of receiving placebo influence clinical trial outcome? A meta-regression of double-blind, randomized clinical trials in MDD.
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      Does inclusion of a placebo arm influence response to active antidepressant treatment in randomized controlled trials? Results from pooled and meta-analyses.
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      Impact of patient selection and study characteristics on signal detection in placebo-controlled trials with antidepressants.
      schizophrenia,
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      Control group bias in randomized atypical antipsychotic medication trials for schizophrenia.
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      Signal detection and placebo response in schizophrenia: parallels with depression.
      and Parkinson disease.
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      • et al.
      Effects of expectation on placebo-induced dopamine release in Parkinson disease.
      Furthermore, increased placebo responses may also account for higher drug responses in comparator studies, in which all patients know they receive a drug either way, compared with placebo-controlled trials, in which patients know that they could receive a placebo only. This association between the probability of receiving a drug and placebo effects has been found for clinical trials of depression
      • Rutherford B.
      • Sneed J.
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      • et al.
      Antidepressant study design affects patient expectancy: a pilot study.
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      • et al.
      Less is more in antidepressant clinical trials: a meta-analysis of the effect of visit frequency on treatment response and dropout.
      and anxiety disorders.
      • Rutherford B.R.
      • Bailey V.S.
      • Schneier F.R.
      • et al.
      Influence of study design on treatment response in anxiety disorder clinical trials.
      Only a few experimental studies, mostly using pain paradigms, have examined differences among disclosed probabilities. For example, healthy participants received an inert infusion with instructions of a 100%, 50%, or 0% probability of receiving an analgesic drug in a visceral pain paradigm.
      • Kotsis V.
      • Benson S.
      • Reidick D.
      • et al.
      Effekte der Erwartungsmodulation auf die viszerale Placeboanalgesie bei gesunden Frauen [Effects of expectation in visceral placebo analgesia: a study in healthy women].
      • Elsenbruch S.
      • Kotsis V.
      • Benson S.
      • et al.
      Neural mechanisms mediating the effects of expectation in visceral placebo analgesia: An fMRI study in healthy placebo responders and nonresponders.
      Participants of the first study reported a significant pain reduction in the 100% compared with the 0% probability condition only,
      • Kotsis V.
      • Benson S.
      • Reidick D.
      • et al.
      Effekte der Erwartungsmodulation auf die viszerale Placeboanalgesie bei gesunden Frauen [Effects of expectation in visceral placebo analgesia: a study in healthy women].
      whereas participants in the second study reported a significant pain decrease in the 100% versus 0% and in the 100% versus 50% probability conditions.
      • Elsenbruch S.
      • Kotsis V.
      • Benson S.
      • et al.
      Neural mechanisms mediating the effects of expectation in visceral placebo analgesia: An fMRI study in healthy placebo responders and nonresponders.
      In a heat pain paradigm, participants received a nasal spray again with the instructions of a 100%, 50%, or 0% probability of receiving an analgesic drug and experienced a significantly higher pain decrease in the 100% versus 0% probability groups and a trend between the 50% versus 0% groups.
      • Rief W.
      • Glombiewski J.A.
      The hidden effects of blinded, placebo-controlled randomized trials: an experimental investigation.
      Nausea is a very common symptom, particularly in oncology and surgery. It is a side effect of many drugs and can occur in otherwise healthy persons as motion sickness in everyday situations, such as traveling by car, bus, or ship. Meta-analyses by Hrobjartsson and Gotzsche
      • Hrobjartsson A.
      • Gotzsche P.C.
      Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment.
      • Hrobjartsson A.
      • Gotzsche P.C.
      Is the placebo powerless? Update of a systematic review with 52 new randomized trials comparing placebo with no treatment.
      • Hrobjartsson A.
      • Gotzsche P.C.
      Placebo interventions for all clinical conditions.
      revealed no significant group-based placebo effect compared with no treatment in RCTs for the treatment of nausea. However, susceptibility of nausea symptoms to placebo (for symptom decrease) and nocebo (for symptom increase) manipulations were noted as early as the 1950s, when Wolf et al
      • Wolf S.
      Effects of suggestion and conditioning on the action of chemical agents in human subjects; the pharmacology of placebos.
      found nausea induction and inhibition with placebo applications in their patient with fistulas.
      • Elsenbruch S.
      • Enck P.
      Placebo effects and their determinants in gastrointestinal disorders.
      Since then, studies about the occurrence of nausea in chemotherapy treatments found that, on the one hand, negative expectations and personal experiences of patients increase anticipatory nausea before chemotherapy
      • Molassiotis A.
      • Lee P.H.
      • Burke T.A.
      • et al.
      Anticipatory nausea, risk factors, and its impact on chemotherapy-induced nausea and vomiting: results from the Pan European Emesis Registry Study.
      and after chemotherapy.
      • Colagiuri B.
      • Zachariae R.
      Patient expectancy and post-chemotherapy nausea: a meta-analysis.
      On the other hand, experimental studies manipulating positive expectations concerning a treatment with an acupressure band
      • Roscoe J.A.
      • O׳Neill M.
      • Jean-Pierre P.
      • et al.
      An exploratory study on the effects of an expectancy manipulation on chemotherapy-related nausea.
      and conditioning with an overshadowing manipulation
      • Stockhorst U.
      • Wiener J.A.
      • Klosterhalfen S.
      • et al.
      Effects of overshadowing on conditioned nausea in cancer patients: an experimental study.
      elicited a decrease in postchemotherapy nausea. Furthermore, experimental studies on motion sickness induced by optokinetic drum or rotation chair repeatedly found that placebo effects elicited through verbal suggestions
      • Levine M.E.
      • Stern R.M.
      • Koch K.L.
      The effects of manipulating expectations through placebo and nocebo administration on gastric tachyarrhythmia and motion-induced nausea.
      • Weimer K.
      • Schulte J.
      • Maichle A.
      • et al.
      Effects of ginger and expectations on symptoms of nausea in a balanced placebo design.
      • Horing B.
      • Weimer K.
      • Schrade D.
      • et al.
      Reduction of motion sickness with an enhanced placebo instruction: an experimental study with healthy participants.
      and through conditioning procedures
      • Klosterhalfen S.
      • Kellermann S.
      • Stockhorst U.
      • et al.
      Latent inhibition of rotation chair-induced nausea in healthy male and female volunteers.
      • Stockhorst U.
      • Hall G.
      • Enck P.
      • Klosterhalfen S.
      Effects of overshadowing on conditioned and unconditioned nausea in a rotation paradigm with humans.
      • Hall G.
      • Stockhorst U.
      • Enck P.
      • Klosterhalfen S.
      Overshadowing and latent inhibition in nausea-based context conditioning in humans: theoretical and practical implications.
      • Quinn V.F.
      • Colagiuri B.
      Sources of placebo-induced relief from nausea: the role of instruction and conditioning.
      can affect nausea.
      Overall, there seems to be a difference in the magnitude of placebo effects on nausea in RCTs compared with experimental studies that could be attributable to the disclosed probability of receiving drug or placebo and to the symptoms’ relevance to the participants. Therefore, we investigated whether the disclosed probability of receiving a drug differentially affects nausea if participants are told that they will definitely receive an antiemetic, will receive an antiemetic in a double-blinded manner, or receive a placebo openly. We assumed a negative linear association between the proposed probability of receiving a drug and nausea, measured as subjective symptoms, behavior (rotation tolerance [RT]), and a biological marker of nausea, the electrogastrogram (EGG). Therefore, our hypothesis is that the higher the disclosed probability, the higher the placebo response. In an experimental rotation chair paradigm, we used volunteers who reported to be at least moderately susceptible to motion sickness in everyday situations and, therefore, are assumed to be personally interested in remedies for symptom reduction. In addition, we explored whether expectations, individual differences in psychological properties, or sex differences will influence placebo responses.

      Methods

      Participants

      Forty-eight healthy participants between 19 and 42 years of age (mean [SD], 26.8 [5.4] years; 50% female) who were recruited at the University of Tübingen took part in this study. They were selected after filling out an online screening questionnaire asking if they were naive to the rotation procedure and had never taken part in any experiment concerning nausea or motion sickness. Women were scheduled during the luteal phase of their menstrual cycle. Furthermore, they must have been moderately susceptible to motion sickness assessed by at least 10 points in the Motion Sickness Susceptibility Questionnaire.
      • Golding J.F.
      Motion sickness susceptibility questionnaire revised and its relationship to other forms of sickness.
      Our sample rated their susceptibility to motion sickness with a mean (SD) of 57.2 (35.5) points, which is slightly higher than published norm values.
      • Golding J.F.
      Motion sickness susceptibility questionnaire revised and its relationship to other forms of sickness.
      The Hospital Anxiety and Depression Scale
      • Herrmann-Lingen C.
      • Buss U.
      • Snaith R.P.
      HADS-D: Hospital Anxiety and Depression Scale - Deutsche Version.
      was used to screen for psychological disorders, and participants were excluded when they reached more than 7 points on the anxiety or depression subscale. Further exclusion criteria were acute or chronic diseases of the central nervous system, the gastrointestinal tract, or the inner ear or other conditions, concomitant medication (except contraceptives), or pregnancy within the last 12 months. They were informed that the purpose of the study was to test the effects of an herbal remedy, which mainly consists of ginger, on motion sickness symptoms.

      Ethics Statement

      The study protocol was approved by the institutional review board of the University Medical School Tübingen, Tübingen, Germany. Participants gave written informed consent before inclusion. The consent form included a so-called authorized deception,
      • Miller F.G.
      • Wendler D.
      • Swartzman L.C.
      Deception in research on the placebo effect.
      (ie, participants were informed that they would be incompletely informed about some details of the study, but there are no more risks than described). Complete disclosure of the study purpose was offered to all participants after completion of the study. This procedure limits ethical concerns about deception of participants and does not affect study outcomes.
      • Martin A.L.
      • Katz J.
      Inclusion of authorized deception in the informed consent process does not affect the magnitude of the placebo effect for experimentally induced pain.

      Study Design

      All participants came to the laboratory twice and underwent the same procedure on both days. Equal numbers of participants of the 3 groups were scheduled at 8 and 10 am for study participations. Day 1 was used to assess individual reactions to the rotation procedure (baseline assessment). At day 2, they were randomly assigned to 1 of 3 experimental groups (Table I) and received the information that (1) they were assigned to the control group and would receive a glass of water only but no ginger remedy (0% expectancy group); (2) this is a double-blinded RCT and they would receive either preparation A or B but without knowing which is the ginger preparation and which is a placebo (50% expectancy group); or (3) they would receive the antiemetic ginger preparation for sure (100% expectancy group).
      Table IExperimental groups.
      GroupInformationPreparationLabel on Bottle
      0% probability“You are in the control group and don’t get any remedy.”Glass of water--
      50% probability“This is a double-blinded study and I don’t know which bottle contains the ginger preparation and which is the placebo.”Glass of water and yellow dropsA or B (2 preparations)
      100% probability“You are lucky, because you are in the experimental group that really gets the ginger remedy!”Glass of water and yellow dropsZintona
      The study preparation was yellow drops that consisted of water colored by food coloring and flavored with lemon taste. This yellow liquid was filled into small brown bottle with pipettes labeled A, B, or the tradename of the ginger extract,
      Trademark: Zintona® (Grünwalder GmbH, Bad Tölz, Germany).
      produced for the University Hospital Tübingen, but all bottles contained the same inert yellow liquid.
      All participants had to drink 200 mL of water before the rotation procedure on each day to have equally filled stomachs for the recording of the EGGs, and 20 drops were added to the water on day 2 if assigned to groups 2 or 3.
      During preparation of the drink, participants were explicitly given some (deceptive) background information about this study: “The ginger remedy tested is called Zintona® (Grünwalder GmbH, Bad Tölz, Germany), is already available on the market as capsules, and has already been successfully tested in a previous study by our group. As ginger is very well tolerated and has nearly no side effects, it is perfectly suitable for the treatment of children, but they have problems taking such big capsules. Therefore, we first perform this pilot study with healthy adults to test the ginger remedy as drops.”

      Experimental Procedure, Subjective Measures, and Behavioral Measures

      For the 2 laboratory visits, participants were scheduled for the same time in the morning (8 or 10 am) with approximately 1 week in between. They were asked to maintain their fast for the last 8 hours before the appointment, and adherence with the fasting instruction was controlled with a glucose stick.
      Similar procedures as the following have already been used by our group in several other studies and have been previously described.
      • Weimer K.
      • Schulte J.
      • Maichle A.
      • et al.
      Effects of ginger and expectations on symptoms of nausea in a balanced placebo design.
      • Horing B.
      • Weimer K.
      • Schrade D.
      • et al.
      Reduction of motion sickness with an enhanced placebo instruction: an experimental study with healthy participants.
      • Klosterhalfen S.
      • Kellermann S.
      • Stockhorst U.
      • et al.
      Latent inhibition of rotation chair-induced nausea in healthy male and female volunteers.
      • Stockhorst U.
      • Hall G.
      • Enck P.
      • Klosterhalfen S.
      Effects of overshadowing on conditioned and unconditioned nausea in a rotation paradigm with humans.
      • Hall G.
      • Stockhorst U.
      • Enck P.
      • Klosterhalfen S.
      Overshadowing and latent inhibition in nausea-based context conditioning in humans: theoretical and practical implications.
      • Klosterhalfen S.
      • Kellermann S.
      • Pan F.
      • et al.
      Effects of ethnicity and gender on motion sickness susceptibility.
      • Klosterhalfen S.
      • Kellermann S.
      • Braun S.
      • et al.
      Gender and the nocebo response following conditioning and expectancy.
      • Weimer K.
      • Horing B.
      • Muth E.R.
      • Enck P.
      How to study placebo responses in motion sickness with a rotation chair paradigm in healthy participants.
      After cutaneous electrodes for the EGG were placed on the surface of their skin above the stomach (see below), participants were seated in a rotation chair. After 15 minutes of baseline EGG recording while sitting in the nonrotating chair, they were asked for the first time to rate 7 symptoms associated with motion sickness (vertigo, headache, nausea, urge to vomit, tiredness, sweating, and stomach awareness) between 0 (none) and 5 (maximal). The same symptom ratings were assessed before rotation, at each interval between 2 runs, immediately after termination and 15 minutes after termination. They were used to calculate a sum symptom rating (SR), ranging from 0 to 35 for baseline and a maximum SR during the rotation procedure.
      Immediately before rotations, participants were blindfolded and then rotated in a standardized fashion for 5 runs of 2 minutes each with 1-minute interruptions in between. Rotation speed was set at 90°/sec (15 rounds per minutes),
      • Horing B.
      • Weimer K.
      • Schrade D.
      • et al.
      Reduction of motion sickness with an enhanced placebo instruction: an experimental study with healthy participants.
      and participants were instructed by earphones to move their head up or down every 10 seconds to enforce the so-called Coriolis effect.
      • Probst T.
      • Schmidt U.
      The sensory conflict concept for the generation of nausea.
      Participants could stop the rotation procedure if severe nausea occurred but were encouraged to continue the next run until 5 runs had at least been started. The total RT was noted as behavioral outcome measure. EGG was recorded for another 15 minutes.

      EGG

      Gastric myoelectrical activity was recorded by an EGG for which 3 skin electrodes were placed above the stomach
      • Miller K.E.
      • Muth E.R.
      Efficacy of acupressure and acustimulation bands for the prevention of motion sickness.
      and connected to a Biolog device with Fetrodes technology (UFI, Morrow Bay, California). The EGG was recorded with a sampling rate of 10 Hz (filter settings: bandpass filter with a low cutoff of 0.0175 Hz and a high cutoff of 0.33 Hz both with 12 dB per octave roll-off) and stored for offline analysis.
      Recordings were screened visually for artifacts. Criteria for artifacts were signals with improbable amplitudes (±1000 μV) for myoelectrical activity of the stomach and fast and sudden onset that did not fit to the surrounding signals. Two segments at least 5 minutes long from recordings at baseline and after rotations were selected for analysis. Selected EGG data were analyzed with a fast Fourier transformation procedure (custom software using Prime Factor fast Fourier transformation for Windows, version 3.03, Alligator Technologies, Costa Mesa, California) and a spectral resolution of 0.29 cycles per minute (cpm). A frequency range of 2.61 to 3.77 cpm was regarded as normal gastric activity (normogastria) and a range of 4.06 to 9.57 cpm as tachygastria. Spectral resolution and frequency bands depend on the sampling rate, which was higher than in most other studies (mostly 5 Hz) and therefore deviate from standard descriptions.
      • Miller K.E.
      • Muth E.R.
      Efficacy of acupressure and acustimulation bands for the prevention of motion sickness.
      • Stern R.M.
      • Koch K.L.
      • Levine M.E.
      • Muth E.R.
      Gastrointestinal response.
      The percentage of spectral power was calculated from the total range of 0.87 to 14.79 cpm (for detailed information see the article by Stern et al,
      • Stern R.M.
      • Koch K.L.
      • Stewart W.R.
      • Lindblad I.M.
      Spectral analysis of tachygastria recorded during motion sickness.
      ) and the ratio between the percentage of the normogastria and tachygastria bands (EGG ratio) as an indicator for nausea was calculated. The interruption of the normal 3-cpm activity of the stomach and a shift toward tachygastria indicated by a decrease of the EGG ratio have been repeatedly associated with nausea (eg, induced by rotation chair or vection drum).
      • Miller K.E.
      • Muth E.R.
      Efficacy of acupressure and acustimulation bands for the prevention of motion sickness.
      • Stern R.M.
      • Koch K.L.
      • Leibowitz H.W.
      • et al.
      Tachygastria and motion sickness.
      EGG data were screened and analyzed by 2 independent raters (K.W., B.H.) and revealed a significant high interrater correlation for the ratio between normogastria and tachygastria (r = .829; P < 0.001).

      Psychological Characteristics and Expectations

      At the beginning of day 1, participants completed questionnaires to assess psychological characteristics that are assumed to affect placebo responses
      • Horing B.
      • Weimer K.
      • Muth E.R.
      • Enck P.
      Prediction of placebo responses: a systematic review of the literature.
      : State-Trait Anxiety Inventory (STAI),
      • Laux L.
      • Glanzmann P.
      • Schaffner P.
      • Spielberger C.D.
      Das State-Trait Angstinventar.
      Life Orientation Test–Revised,
      • Glaesmer H.
      • Hoyer J.
      • Klotsche J.
      • Herzberg P.Y.
      The German version of the Life-Orientation-Test (LOT-R) for dispositional optimism and pessimism.
      General Self-Efficacy scale,
      • Schwarzer R.
      • Jerusalem M.
      Skalen zur Erfassung von Lehrer- und Schu¨lermerkmalen. Dokumentation der psychometrischen Verfahren im Rahmen der wissenschaftlichen Begleitung des Modellversuchs Selbstwirksame Schulen [Scales to assess teacher and student characteristics. Documentation of psychometric methods in the context of scientific monitoring of the model experiment ‘‘Self-efficacious schools’’].
      Proactive Coping Inventory,

      Schwarzer R, Greenglass E, Taubert S. PCI - Fragebogen zu allgemeiner und proaktiver Stressbewältigung: Deutsche Testversion I (2000) des Proactive Coping Inventory 2000 [http://userpage.fu-berlin.de/~health/pcigerman1.htm; Accessed 08/12/2016].

      Fragebogen zu Kompetenz- und Kontrollüberzeugungen (a scale for competence and control beliefs),
      • Krampen G.
      Fragebogen zu Kompetenz- und Kontrollüberzeugungen (FKK).
      ) and the Pavlovian Temperament Scale.
      • Strelau J.
      • Angleitner A.
      Cross-cultural studies on temperament: theoretical considerations and empirical studies based on the Pavlovian Temperament Survey.
      For a detailed description of the questionnaires and their use and effects in other placebo studies, see our previous publications.
      • Horing B.
      • Weimer K.
      • Muth E.R.
      • Enck P.
      Prediction of placebo responses: a systematic review of the literature.
      • Horing B.
      • Weimer K.
      • Muth E.R.
      • Enck P.
      Prediction of symptom change in placebo versus no-treatment group in experimentally induced motion sickness.
      In short, the STAI
      • Laux L.
      • Glanzmann P.
      • Schaffner P.
      • Spielberger C.D.
      Das State-Trait Angstinventar.
      contains 2 questionnaires to assess anxiety as a trait (STAI-T) and as a current state (STAI-S). Both versions have 20 items to be rated between 1 (not at all) and 4 (very much), and values have to be summed up after recoding of single items. The Life Orientation Test–Revised assesses dispositional optimism with 10 items of which 4 are only included to distract participants. After recoding, the remaining items can be used to calculate an overall optimism score.
      • Glaesmer H.
      • Hoyer J.
      • Klotsche J.
      • Herzberg P.Y.
      The German version of the Life-Orientation-Test (LOT-R) for dispositional optimism and pessimism.
      Items are rated between 0 (not at all) and 4 (very much). The General Self-Efficacy scale asks for the subjective ability to cope with difficult situations.
      • Schwarzer R.
      • Jerusalem M.
      Skalen zur Erfassung von Lehrer- und Schu¨lermerkmalen. Dokumentation der psychometrischen Verfahren im Rahmen der wissenschaftlichen Begleitung des Modellversuchs Selbstwirksame Schulen [Scales to assess teacher and student characteristics. Documentation of psychometric methods in the context of scientific monitoring of the model experiment ‘‘Self-efficacious schools’’].
      The questionnaire contains 10 items to be answered between 1 (not true) to 4 (really true), and the sum is calculated. The Proactive Coping Inventory is one scale of a larger inventory and assesses whether a person applies an effective proactive style to cope with occurring problems.

      Schwarzer R, Greenglass E, Taubert S. PCI - Fragebogen zu allgemeiner und proaktiver Stressbewältigung: Deutsche Testversion I (2000) des Proactive Coping Inventory 2000 [http://userpage.fu-berlin.de/~health/pcigerman1.htm; Accessed 08/12/2016].

      It contains 17 items that are answered on a 4-point Likert scale and summed. The Fragebogen zu Kompetenz- und Kontrollüberzeugungen
      • Krampen G.
      Fragebogen zu Kompetenz- und Kontrollüberzeugungen (FKK).
      measures locus of control through 32 items that are rated between 0 and 6 points on 4 scales for an internal locus of control, powerful others, chance control, and generalized self. The Pavlovian Temperament Scale
      • Strelau J.
      • Angleitner A.
      Cross-cultural studies on temperament: theoretical considerations and empirical studies based on the Pavlovian Temperament Survey.
      evaluates cognitive abilities on 3 scales: strength of inhibition, mobility of nervous processes, and strength of excitation. Each scale comprises 24 items rated on a 4-point scale, and sums were calculated.
      On day 2, participants were asked to rate their expected susceptibility to rotation stimuli (expectation value) on a visual analog scale (VAS) between 0 and 100 (0, not susceptible; 100, maximum susceptibility) 3 times: at the beginning of the appointment, before the rotation procedure, and after the rotation procedure.

      Statistical Analysis

      Outcome measures as indicators of a placebo response were the maximum SR corrected by the initial SR, the RT, and the ratio of the normogastria to tachygastria bands of the EGG (EGG ratio). Equal distribution of demographic and other characteristics before intervention among the 3 experimental groups were tested by ANOVAs and χ2 tests (Table II). To test whether the disclosed information affects outcome measures on day 2, groups were compared with 2 × 3 repeated-measures ANOVAs (days × groups) for SR and RT, respectively, and 2 × 2 × 3 repeated-measures ANOVAs (day × time × groups) for the EGG ratio. For post hoc analyses, t tests were performed and the Levene test considered.
      Table IIBaseline assessments and psychological characteristics of participants (M ± SD or n, respectively).
      100% probability50% probability0% probabilityP
      Gender (n; f:m)8:88:88:81.0
      Age (years)28.3 ± 6.427.1 ± 4.925.2 ± 4.70.277
      BMI (kg/m2)25.0 ± 4.522.8 ± 3.322.8 ± 2.80.143
      MSSQ62.7 ± 40.065.4 ± 40.843.4 ± 19.20.162
      HADS-A4.00 ± 1.714.25 ± 1.843.62 ± 2.190.655
      HADS-D1.81 ± 1.472.00 ± 1.672.69 ± 2.240.369
      STAI-T33.8 ± 7.633.0 ± 7.233.9 ± 7.20.936
      STAI-S32.4 ± 3.731.9 ± 3.332.1 ± 2.70.902
      LOT-R17.4 ± 4.818.0 ± 3.717.5 ± 3.20.908
      PCI48.4 ± 6.851.9 ± 7.151.7 ± 5.90.267
      GSE29.2 ± 4.530.6 ± 3.730.3 ± 2.70.527
      PTS scale 12.55 ± 0.412.63 ± 0.242.60 ± 0.340.804
      PTS scale 22.88 ± 0.563.20 ± 0.362.98 ± 0.420.141
      PTS scale 32.43 ± 0.482.66 ± 0.392.45 ± 0.330.226
      FKK-I23.5 ± 6.324.3 ± 5.224.9 ± 4.50.769
      FKK-C11.3 ± 4.415.7 ± 5.415.6 ± 5.90.033a
      FKK-P16.0 ± 5.314.3 ± 4.516.9 ± 4.70.323
      FKK-SC26.4 ± 5.428.1 ± 4.825.6 ± 5.20.381
      SR0 t11.38 ± 1.202.00 ± 1.511.56 ± 1.460.436
      RT t1 (in sec)451 ± 175396 ± 179414 ± 1950.690
      SR0 t21.25 ± 1.132.38 ± 2.161.25 ± 1.480.094
      Notes: a significant differences between 100% and 0%, and between 100% and 50% groups. BMI=Body Mass Index, MSSQ=Motion Sickness Susceptibility Questionnaire, HADS=Hospital Anxiety and Depression Scale (A=anxiety, D=depression), STAI=State-Trait Anxiety Inventory (S=state, T=trait), LOT-R=Life Orientation Test-Revised, PCI=Proactive Coping Inventory, GSE=General Self-efficacy Scale, PTS=Pavlovian Temperament Scales (1=strength of inhibition, 2=mobility of nervous processes, 3=strength of excitation), FKK=Questionnaire for competence and control beliefs (I=internal locus of control, C=chance control, P=powerful others, SC=generalized self concept), SR=symptom rating, t1=day 1, t2=day2.
      A priori sample size calculations revealed required sample sizes of 42 participants for 2 × 3 repeated-measures ANOVAs for SR and RT and 30 participants for 2 × 2 × 3 repeated-measures ANOVA for the EGG ratio. Sample size calculations were performed with G*Power version 3.1.7 (Franz Faul, University of Kiel, Kiel, Germany) for an effect size of f = 0.25, α = 0.05, and power = 0.80.
      To investigate whether subjectively rated expectations about the susceptibility to motion sickness mediate the effect of disclosed probabilities on outcome measures, mediation analyses according to Hayes and Preacher
      • Hayes A.F.
      • Preacher K.J.
      Statistical mediation analysis with a multicategorial independent variable.
      were performed. They provide a macro for SPSS (PROCESS) to investigate mediation analyses with a multicategorial independent variable based on 5000 bootstrap samples to assess bias corrected bootstrap CIs.
      • Hayes A.F.
      • Preacher K.J.
      Statistical mediation analysis with a multicategorial independent variable.
      Group membership is indicator (dummy) coded by the macro with the 0% probability group treated as the reference group. The mediation is assumed to be significant when the distribution of the bootstrapped relative indirect effects is located within a 95% CI not containing zero. Relative indirect effects can be interpreted as units of change in the outcome mediated through expectations when group membership differs by one unit, meaning a comparison between participants who are in one experimental group (100% or 50% probability) compared with the reference group (0% probability). Psychological characteristics as predictors of placebo responses were analyzed with moderator analyses according to Baron and Kenny.
      • Baron R.M.
      • Kenny D.A.
      The moderator-mediator variable distinction in social psychological research: conceptual, strategic, and statistical considerations.
      Group membership, the psychological variable, and the interaction term of both were entered in multiple regression analyses. Moderator and mediator analyses were planned for ΔSR, ΔRT, and ΔEGG ratio (differences between day 1 and 2) as dependent variables but were performed for ΔSR only because of a lack of significant placebo effects on ΔRT and ΔEGG ratio.
      To explore the effects of sex of participants on the results, post hoc analyses were performed by including sex as a factor in analyses and by analyzing data separately for women and men.
      The significance level was set to α = .05, and P values between 0.051 and 0.100 were considered to indicate a trend. All analyses were performed with IBM SPSS Statistics for Windows, version 19.0 (IBM Corp, Armonk, New York).

      Results

      Baseline Assessments

      Table II gives the baseline assessments and psychological characteristics of the 3 experimental groups, which did not significantly differ in variables that were relevant for study inclusion (age, Motion Sickness Susceptibility Questionnaire, Hospital Anxiety and Depression Scale). Furthermore, they did not differ in sex distribution, body mass index, psychological characteristics, and symptom ratings before rotation procedures. The significant difference between groups for one Fragebogen zu Kompetenz- und Kontrollüberzeugungen subscale was considered to be by chance.

      Effects of the Disclosed Probability

      SR significantly decreased in all 3 groups (F1,45 = 35.070, P < 0.001) with a significant difference between groups (F2,45 = 5.473, P = 0.007). Post hoc t tests with the difference in SR from day 1 to day 2 as the dependent variable (ΔSR) revealed a significantly stronger decrease in symptoms in the 50% compared with the 0% expectancy group (t30 = −3.142, P = 0.004) and a trend for a stronger decrease in symptoms in the 100% compared with the 0% expectancy group (t30 = −1.964, P = 0.059) but no difference between 100% and 50% expectancy groups (t30 = 1.522, P = 0.139). Combining the 100% and 50% expectancy groups revealed a significant lower SR compared with the 0% expectancy group (t46 = −2.813, P = 0.007) (Figure 1).
      Figure 1
      Figure 1Maximum symptom ratings in the experimental groups on days 1 and 2. Error bars indicate SE. *P < 0.01, P < 0.10.
      Analyses for RT revealed a significant increase in all 3 groups (F1,45 = 9.458, P = 0.004), but groups did not differ (F2,45 = 0.364, P = 0.769) (Figure 2).
      Figure 2
      Figure 2Rotation tolerance (RT) in the experimental groups on days 1 and 2. Error bars indicate SE.

      Gastric Myoelectrical Activity

      Because of movement artifacts on at least 1 of the 4 EGG recording periods, complete data were available from 29 participants only (60.4%). Table III gives the values of the EGG ratios of the 29 participants and the maximal available EGG ratios for the 4 recording periods and the number of participants. Eliminated data were equally distributed across the experimental groups (χ2 = 2.265, P = 0.322). The 2 × 2 × 3 ANOVA was not significant (F2,26 = 0.088, P = 0.650), but there was a significant decrease of the EGG ratio from before to after rotations in all groups on both days (F1,26 = 7.049, P = 0.013), indicating a shift toward tachygastria in all participants (Table III).
      Table IIISubjective rating of susceptibility to rotation stimuli on day 2, at baseline (expectancy value; EV1), prior (EV2) and after (EV3) rotations on a 0 to 100 VAS (M ± SD).
      100% expectancy50% expectancy0% expectancyP
      EV165.1 ± 22.555.6 ± 24.656.0 ± 22.00.426
      EV267.0 ± 21.457.1 ± 26.456.2 ± 21.20.350
      EV363.1 ± 29.161.8 ± 25.769.4 ± 23.90.679
      Notes: EV=expectancy value.

      Mediation Analyses for Subjective Expectations

      Subjectively rated expectations about the susceptibility to motion sickness at the beginning of the appointment and immediately before the rotation procedure did not differ between groups (F2,45 = 0.870, P = 0.426, and F2,45 = 1.073, P = 0.350, respectively) (Table IV). All relative indirect effects of both the 50% and 100% probability groups each compared with the 0% group on ΔSR through expectations at the beginning (relative indirect effects of −0.001 and 0.029) and through expectations before rotations (relative indirect effects of 0.006 and 0.065) were not significant, indicating that subjective expectations did not mediate placebo effects.
      Table IVRatio of normogastria to tachygastria bands during the four recording periods prior and post rotations (pre, post) on both days (t1, t2) in experimental groups.
      100% expectancy50% expectancy0% expectancyP
      EGG data available at all four recording periods
      n89120.322 a
      Ratio pre, t11.01 ± 0.361.18 ± 0.501.18 ± 0.630.743
      Ratio post, t10.83 ± 0.400.89 ± 0.300.67 ± 0.240.269
      Ratio pre, t21.05 ± 0.481.12 ± 0.621.09 ± 0.300.961
      Ratio post, t20.85 ± 0.361.01 ± 0.510.95 ± 0.480.778
      Maximal available EGG data at the four recording periods
      Ratio pre, t10.94 ± 0.37 (n=16)1.02 ± 0.44 (n=16)1.17 ± 0.72 (n=16)0.449
      Ratio post, t10.81 ± 0.38 (n=10)0.87 ± 0.32 (n=12)0.69 ± 0.25 (n=13)0.377
      Ratio pre, t21.16 ± 0.60 (n=12)0.98 ± 0.52 (n=15)1.13 ± 0.40 (n=15)0.596
      Ratio post, t20.79 ± 0.35 (n=10)0.89 ± 0.50 (n=12)0.93 ± 0.47 (n=13)0.758
      Note: a Χ2 test. EGG=Electrogastrogram data.

      Placebo Response Prediction Through Psychological Characteristics

      Multiple moderated regression analyses revealed that none of the psychological characteristics assessed in this study moderated placebo effects on ΔSR.

      Sex Differences

      In an exploratory way, post hoc analyses were performed to test whether sex of participants had an effect on placebo effects. Including sex of participants, the 2 × 3 × 2 ANOVA (day × group × sex) revealed no interactional effect for SR (F2,42 = 0.906, P = 0.412). When data were analyzed separately for women and men, 2 × 3 ANOVAs revealed significant main effects for day with a symptom decrease from day 1 to day 2 in both women (F1,21 = 22.867, P < 0.001) and men (F1,21 = 12.624, P = 0.002). However, the interaction effect of day × group reveals that groups significantly differed in SR in women only (F2,21 = 4.981, P = 0.017) but not in men (F2,21 = 1.353, P = 0.280).
      In women, post hoc t tests revealed significant differences in ΔSR between the 100% and 0% probability groups (t14 = −2.275, P = 0.039) and between the 50% and 0% probability groups (t14 = −2.994, P = 0.010) but not between the 100% and 50% probability groups (t14 = 1.014, P = 0.328). When combined, the 100% and 50% expectancy groups were significantly different from the 0% expectancy group (t22 = −2.957, P = 0.007). In men, all group differences were not significant. Figure 3A and B show results of post hoc t tests for SR in women and men in the 3 experimental groups on both days.
      Figure 3
      Figure 3Maximum symptom ratings (SRs) in the experimental groups on days 1 and 2 for women (A) and men (B). Error bars indicate SE. Asterisks flag significant differences in ∆SR between groups: *P < 0.05, P < 0.01.
      Concerning RT, groups did not differ when sex of participants was included as a factor in the ANOVA or when separate analyses for women and men were performed (data not shown). Concerning the EGG ratio, examining sex differences revealed no significant interaction in the 2 × 2 × 3 × 2 ANOVA or in separate ANOVAs for women and men (data not shown). Dropouts in the EGG data were equally distributed among women and men.
      Mediation and moderation analyses for women and men separately revealed no significant mediation of subjective expectations on placebo effects and no significant moderator effect on psychological characteristics.

      Discussion

      The aim of this study was to examine, for the first time with a nausea paradigm, whether different instructions concerning the probability of receiving an antiemetic affects placebo responses on nausea in an experimental study with participants susceptible to motion sickness. Particularly, we asked whether there was a difference between placebo effects in classic 2-group double-blinded RCTs, in which participants know that they have a 50% probability to receive the drug or placebo, and placebo responses in experimental placebo studies, in which participants are deceptively told that they will definitely receive a drug. We found that both disclosed probabilities compared with a baseline assessment with no instruction and compared with a group, which was given the information that they would not receive an antiemetic, significantly reduced symptoms of nausea in equal measure. In agreement with the literature about experimental placebo studies
      • Quinn V.F.
      • Colagiuri B.
      Placebo interventions for nausea: a systematic review.
      and in contrast to meta-analysis of RCTs,
      • Hrobjartsson A.
      • Gotzsche P.C.
      Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment.
      • Hrobjartsson A.
      • Gotzsche P.C.
      Is the placebo powerless? Update of a systematic review with 52 new randomized trials comparing placebo with no treatment.
      • Hrobjartsson A.
      • Gotzsche P.C.
      Placebo interventions for all clinical conditions.
      we found that in general nausea is susceptible to placebo effects by instructions only (that is, above a pure learning or habituation effect). However, we could not confirm the hypothesis of a linear association between disclosed probability and symptom reduction
      • Enck P.
      • Klosterhalfen S.
      • Weimer K.
      • et al.
      The placebo response in clinical trials: more questions than answers.
      • Diener H.C.
      • Dowson A.J.
      • Ferrari M.
      • et al.
      Unbalanced randomization influences placebo response: scientific versus ethical issues around the use of placebo in migraine trials.
      or of conceptual differences between RCTs and placebo studies
      • Vase L.
      • Riley 3rd, J.L.
      • Price D.D.
      A comparison of placebo effects in clinical analgesic trials versus studies of placebo analgesia.
      because we did not find any difference between the 100% and 50% probability groups. Furthermore, we found the response to be exclusively on the subjective symptom level and neither for a behavioral measure of nausea (RT) nor for a nausea biomarker (in the EGG).
      One explanation for the lack of a significant difference between the 100% and 50% probability groups could be that our participants had already shown a learning or habituation effect from day 1 to day 2, and the additional effect of different instructions was not strong enough to differentiate between them. Furthermore, many of the participants were medical students and may have asked themselves why we told them that they would definitely receive an antiemetic because this is unusual for clinical trials. In such cases, the experimenter answered that we wanted to test the efficacy in real-life situations in which patients also know which drugs they take; however, this explanation may not have been convincing for all participants. In addition, although we tried to simulate the unequal situations of an RCT and a study about placebo mechanisms through different instructions,
      • Vase L.
      • Riley 3rd, J.L.
      • Price D.D.
      A comparison of placebo effects in clinical analgesic trials versus studies of placebo analgesia.
      we performed an experimental study. Finally, different mechanisms could come into operation when disclosed probabilities are varying (ie, when there is a degree of uncertainty or security about the content). At least for patients with Parkinson disease, de la Fuente-Fernandez et al
      • de la Fuente-Fernandez R.
      • Schulzer M.
      • Stoessl A.J.
      Placebo mechanisms and reward circuitry: clues from Parkinson׳s disease.
      proposed the placebo-reward hypothesis stating that “the placebo effect is related to the activation of the reward circuitry” and that the activation of the reward circuitry is related to the probability of receiving an active treatment in a reverse U-shaped manner. Therefore, placebo effects were highest with a 50% probability (ie, the highest uncertainty) of receiving the active treatment but lowest when the probability is 0 or 1 in their paradigm. In a later article,
      • de la Fuente-Fernandez R.
      The placebo-reward hypothesis: dopamine and the placebo effect.
      they argued that other mechanisms may have come into effect with no uncertainty (eg, trust in the physician-patient relationship in real life situations, which enhances expectations). It has been proposed that the release of oxytocin, a hormone closely related to social behavior and interpersonal trust, could be such a mechanism,
      • Enck P.
      • Klosterhalfen S.
      The story of O--is oxytocin the mediator of the placebo response?.
      and exogenous oxytocin
      • Kessner S.
      • Sprenger C.
      • Wrobel N.
      • et al.
      Effect of oxytocin on placebo analgesia: a randomized study.
      and the related vasopressin
      • Colloca L.
      • Pine D.S.
      • Ernst M.
      • et al.
      Vasopressin boosts placebo analgesic effects in women: a randomized trial.
      enhance placebo effects in experimental pain studies. Oxytocin is related to the dopamine system in a sex-specific manner because genetic variations of oxytocin-regulating genes are related to pain stress–induced dopamine release in women but not in men,
      • Love T.M.
      • Enoch M.A.
      • Hodgkinson C.A.
      • et al.
      Oxytocin gene polymorphisms influence human dopaminergic function in a sex-dependent manner.
      which could explain sex differences in our study, too. Dopamine also explains 25% of the variance in placebo analgesia,
      • Scott D.J.
      • Stohler C.S.
      • Egnatuk C.M.
      • et al.
      Placebo and nocebo effects are defined by opposite opioid and dopaminergic responses.
      but the roles of dopamine, as well as oxytocin and other putative neuroendocine placebo mediators, in nausea and motion sickness have not yet been examined.
      Explicit expectations concerning the subjective susceptibility to motion sickness did not significantly differ between groups and did not mediate the effects of the disclosed probability on symptom reduction in our study. The effect of an activated reward circuitry through high uncertainty in the 50% group could be as effective as the effect of trust in a secure treatment, leading to placebo responses in both conditions without explicit expectations. Another experimental study on motion sickness revealed that a feeling of control and predictability of the experimental situation could attenuate the development of nausea.
      • Levine M.E.
      • Stern R.M.
      • Koch K.L.
      Enhanced perceptions of control and predictability reduce motion-induced nausea and gastric dysrhythmia.
      Although they did not use any intervention, this study points toward the fact that predictability of a situation with low uncertainty could have an effect on symptoms itself.
      Meta-analyses
      • Hrobjartsson A.
      • Gotzsche P.C.
      Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment.
      • Hrobjartsson A.
      • Gotzsche P.C.
      Is the placebo powerless? Update of a systematic review with 52 new randomized trials comparing placebo with no treatment.
      • Hrobjartsson A.
      • Gotzsche P.C.
      Placebo interventions for all clinical conditions.
      of RCTs on nausea did not reveal a significant effect of placebo compared with a no treatment group, which led them conclude that any placebo effect in nausea is clinically irrelevant. However, in most of the studies included in the meta-analyses, patients received a basic antiemetic medication, and the (placebo) intervention tested to reduce nausea was an add-on in patients undergoing surgery or chemotherapy
      • Dundee J.W.
      • Chestnutt W.N.
      • Ghaly R.G.
      • Lynas A.G.
      Traditional Chinese acupuncture: a potentially useful antiemetic?.
      • Shen J.
      • Wenger N.
      • Glaspy J.
      • et al.
      Electroacupuncture for control of myeloablative chemotherapy-induced emesis: A randomized controlled trial.
      • Alkaissi A.
      • Evertsson K.
      • Johnsson V.A.
      • et al.
      P6 acupressure may relieve nausea and vomiting after gynecological surgery: an effectiveness study in 410 women.
      • Bushunow P.
      • Matteson S.
      • Morrow G.A.
      • et al.
      Acustimulation wristbands for the relief of chemotherapy-induced nausea.
      ; therefore, these findings are not comparable to our paradigm and data.
      In our study, placebo responses by verbal suggestions were found to reduce subjective symptoms of nausea but did not affect behavioral (RT) or physiologic (gastric myoelectrical activity) measures. Furthermore, post hoc analyses confirmed this result to be valid for women only. Most placebo studies with nausea induced by verbal suggestions assessed several outcomes and found mixed results
      • Quinn V.F.
      • Colagiuri B.
      Placebo interventions for nausea: a systematic review.
      . Whereas Levine et al
      • Levine M.E.
      • Stern R.M.
      • Koch K.L.
      The effects of manipulating expectations through placebo and nocebo administration on gastric tachyarrhythmia and motion-induced nausea.
      are the only ones who found a (reversed) placebo effect on all 3 kinds of outcomes in healthy participants, others found effects on SR and an objective rating of behavior in male naval recruits,
      • Eden D.
      • Zuk Y.
      Seasickness as a self-fulfilling prophecy: raising self-efficacy to boost performance at sea.
      on SR and antiemetic use in female patients undergoing chemotherapy,
      • Roscoe J.A.
      • O׳Neill M.
      • Jean-Pierre P.
      • et al.
      An exploratory study on the effects of an expectancy manipulation on chemotherapy-related nausea.
      on SR in male but not female participants,
      • Quinn V.F.
      • Colagiuri B.
      Sources of placebo-induced relief from nausea: the role of instruction and conditioning.
      on RT but not on SR in male but not female participants
      • Klosterhalfen S.
      • Kellermann S.
      • Braun S.
      • et al.
      Gender and the nocebo response following conditioning and expectancy.
      (experiment 2), or on EGG but not SR in all participants.
      • Williamson M.J.
      • Thomas M.J.
      • Stern R.M.
      The contribution of expectations to motion sickness symptoms and gastric activity.
      Horing et al
      • Horing B.
      • Weimer K.
      • Schrade D.
      • et al.
      Reduction of motion sickness with an enhanced placebo instruction: an experimental study with healthy participants.
      found an effect on SR, RT, and head movements in multivariate analyses and did not find any sex differences. Levine et al
      • Levine M.E.
      • Stern R.M.
      • Koch K.L.
      The effects of manipulating expectations through placebo and nocebo administration on gastric tachyarrhythmia and motion-induced nausea.
      and Williamson et al
      • Williamson M.J.
      • Thomas M.J.
      • Stern R.M.
      The contribution of expectations to motion sickness symptoms and gastric activity.
      do not report whether they tested for sex differences.
      Overall, most of these studies found placebo effects on subjective or behavioral measures (SR, RT, head movements (HM)) but not on physiologic responses (EGG). This is in accordance with placebo studies with pain and other symptoms in which both a central and a peripheral component are assumed. In general, placebo responses come into effect via a central mechanism through expectations and learning mechanisms,
      • Enck P.
      • Bingel U.
      • Schedlowski M.
      • Rief W.
      The placebo response in medicine: minimize, maximize or personalize?.
      although involvement of peripheral pathways have also been shown (eg, in the conditioning of immune functions).
      • Schedlowski M.
      • Enck P.
      • Rief W.
      • Bingel U.
      Neuro-bio-behavioral mechanisms of placebo and nocebo responses: implications for clinical trials and clinical practice.
      In our study, we could detect sex differences in placebo effects on motion sickness by verbal suggestions, when data were analyzed separately for women and men
      • Quinn V.F.
      • Colagiuri B.
      Sources of placebo-induced relief from nausea: the role of instruction and conditioning.
      but not when sex was included as a factor in ANOVAs
      • Horing B.
      • Weimer K.
      • Schrade D.
      • et al.
      Reduction of motion sickness with an enhanced placebo instruction: an experimental study with healthy participants.
      because our study was not powered for these exploratory analyses. However, according to our recently published review on sex differences in the placebo effect,
      • Weimer K.
      • Enck P.
      • Klosterhalfen S.
      Geschlechtseffekte bei der Placeboresponse [Gender effects in placebo response].
      results are inconclusive for placebo effect by verbal suggestions on nausea and motion sickness, too. Klosterhalfen et al
      • Klosterhalfen S.
      • Kellermann S.
      • Braun S.
      • et al.
      Gender and the nocebo response following conditioning and expectancy.
      found men to be susceptible to nocebo effects (symptom worsening) by verbal suggestions. Quinn and Colagiuri
      • Quinn V.F.
      • Colagiuri B.
      Sources of placebo-induced relief from nausea: the role of instruction and conditioning.
      found men only to be susceptible to placebo effects. We found women only to be susceptible to placebo effects. Furthermore, there could be an interassociation with the sex of the experimenter, as shown in one of our previous studies.
      • Weimer K.
      • Schulte J.
      • Maichle A.
      • et al.
      Effects of ginger and expectations on symptoms of nausea in a balanced placebo design.
      In contrast to a previously published report about psychological predictors of the placebo responses in general
      • Horing B.
      • Weimer K.
      • Muth E.R.
      • Enck P.
      Prediction of placebo responses: a systematic review of the literature.
      and a study about placebo effects on nausea,
      • Horing B.
      • Weimer K.
      • Muth E.R.
      • Enck P.
      Prediction of symptom change in placebo versus no-treatment group in experimentally induced motion sickness.
      we could not confirm any of the predictors assessed for placebo responses in this study.
      There are some limitations concerning our study that should be mentioned. First, we did not test other ratios of randomization than 1:1 for drug to placebo instructions as others did
      • Lidstone S.C.
      • Schulzer M.
      • Dinelle K.
      • et al.
      Effects of expectation on placebo-induced dopamine release in Parkinson disease.
      ; therefore, the association between different expectation likelihoods may as well be nonlinear. Second, questions about expectations were phrased equally in all groups despite different information provided, and participants were asked the same questions at all 3 occasions (at the beginning of the appointment, immediately before the rotation procedure, and after the rotation procedure): how they assess their susceptibility for rotation stimuli at that moment (on a VAS). Following a suggestion by Vase et al
      • Vase L.
      • Robinson M.E.
      • Verne G.N.
      • Price D.D.
      The contributions of suggestion, desire, and expectation to placebo effects in irritable bowel syndrome patients.
      to differentiate between (cognitive) expectations and (emotional) desire, we considered asking how much they desired to have a reduced susceptibility or whether the remedy would work. However, we expected that such questioning could lead to ambiguous effects, particularly in the 0% probability group, and decided to not vary the questioning in the groups to allow comparability. To take the desire for a positive, symptom-relieving effect into account, we instead included only participants with high susceptibility for motion sickness. Third, most of the participants were healthy students who could be a too homogenous group concerning psychological variables, which made it more difficult to detect moderators of placebo effects. Finally, post hoc analyses separately for women and men and analyses of EGG data may have been underpowered because there were only 8 people left in some subgroups, and there were substantial dropout rates for the EGG data.
      In summary, we found that nausea and motion sickness are susceptible to placebo effects by verbal suggestions alone. Concerning nausea, there seems to be no difference between the probability to receive an antiemetic for sure, as in most experimental placebo studies, and a 50% probability, as in most RCTs. Our results were valid for women only, and the chosen variables assessed could not further predict these results. Future studies should take ratios other than a 1:1 randomization into account to test the linear or nonlinear association between disclosed probability and placebo effects and the underlying mechanisms, such as the involvement of the dopamine and oxytocin system, in the antiemetic placebo response. Furthermore, future studies should include open-label placebo groups, which could receive either the information that the placebo treatment probably will decrease symptoms or the information that the placebo treatment probably will not decrease symptoms. Recent studies have found that open-label placebos can reduce symptom severity in irritable bowel syndrome
      • Kaptchuk T.J.
      • Friedlander E.
      • Kelley J.M.
      • et al.
      Placebos without deception: a randomized controlled trial in irritable bowel syndrome.
      and low back pain,
      • Carvalho C.
      • Caetano J.M.
      • Cunha L.
      • et al.
      Open-label placebo treatment in chronic low back pain: a randomized controlled trial.
      which provide the possibility of placebo use without deception of patients. Our results support implications for the treatment and management of nausea in different medical contexts. The communicated certainty about a treatment could enhance the management of patients’ expectations and affect nausea in mild but widespread conditions, such as motion sickness, which occurs in nearly all healthy persons under certain circumstances. Probably, it could also affect nausea in more severe conditions, such as chemotherapy-induced nausea and vomiting, which are also susceptible to placebo and nocebo effects, as has already been reported by others.
      • Colagiuri B.
      • Zachariae R.
      Patient expectancy and post-chemotherapy nausea: a meta-analysis.
      • Roscoe J.A.
      • O׳Neill M.
      • Jean-Pierre P.
      • et al.
      An exploratory study on the effects of an expectancy manipulation on chemotherapy-related nausea.
      • Stockhorst U.
      • Wiener J.A.
      • Klosterhalfen S.
      • et al.
      Effects of overshadowing on conditioned nausea in cancer patients: an experimental study.
      KW was involved in study design, and performed all study appointments, statistical analyses, interpreted the data, and drafted the manuscript. PE and SK planned the study, applied for funding, and supervised the study. ERM was involved in study design and analyzing of EGG data. BH and JLS helped analyzing EGG data. All authors read and approved the final version of the manuscript for publication.

      Funding Sources

      This work was supported by the Volkswagen Foundation, Hannover, Germany (grant I/83 805), and by the German Research Foundation (grant WE 5658/2-1).

      Conflicts Of Interest

      The authors have indicated that they have no conflicts of interest regarding the content of this article.

      Acknowledgments

      KW was involved in study design, and performed all study appointments, statistical analyses, interpreted the data, and drafted the manuscript. PE and SK planned the study, applied for funding, and supervised the study. ERM was involved in study design and analyzing of EGG data. BH and JLS helped analyzing EGG data. All authors read and approved the final version of the manuscript for publication.

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